Síntese de álcoois secundários quirais via resolução cinética dinâmica quimioenzimática
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Data
2019-02-27
Autores
Almeida, Laíza Araujo de
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Universidade Estadual Paulista (Unesp)
Resumo
Álcoois secundários opticamente ativos são blocos construtores para diversos produtos farmacêuticos, agroquímicos e alimentícios. Apesar da quantidade de metodologias já descritas na literatura para sua obtenção, ainda é necessária a busca por metodologias sustentáveis e de maior custo-benefício. Neste contexto, esse trabalho visou o desenvolvimento de uma nova metodologia de resolução cinética dinâmica (RCD) quimioenzimática para a obtenção de álcoois secundários enantiomericamente puros. Para isso, estudou-se inicialmente a etapa de racemização avaliando o sulfato de vanadila hidratado (VOSO4) como catalisador. O VOSO4 se mostrou muito eficiente, racemizando o substrato modelo (S)-(−)-1feniletanol em apenas 30 minutos (ee(S) = 1,0%; octano, 80 ºC). Em seguida, as condições reacionais da racemização foram otimizadas variando solvente, temperatura e quantidade de catalisador, sendo estabelecido como condição ótima a reação em heptano a 50 ºC (ee(S) = 4,6%). Além disso, por se tratar de um catalisador heterogêneo, foi avaliado também a reciclabilidade de VOSO4 e este se mostrou extremamente ativo mesmo após 10 ciclos consecutivos de racemização. As reações de RCD foram então realizadas na condição reacional ótima, utilizando rac-1feniletanol como substrato modelo, lipase de Candida antarctica B imobilizada (CALB) como catalisador enantiosseletivo, VOSO4 como agente de racemização e avaliando-se diferentes doadores de acila. A reação realizada com decanoato de vinila foi a mais eficiente, resultando na formação do produto (R)-decanoato de 1-feniletila com 87% de conversão e ee > 99%. Entretanto, na avaliação da reciclabilidade do sistema quimioenzimático heterogêneo, observou-se uma perda significativa da atividade catalítica já no segundo ciclo reacional. Por fim, na avaliação da aplicabilidade do protocolo de RCD desenvolvido para uma série de álcoois secundários, observou-se altas conversões (71 a >99%) e excelentes excessos enantioméricos (>99%) com álcoois aromáticos para-substituídos e heteroatomáticos como substratos, porém os substratos com substituintes na cadeia lateral não foram convertidos aos ésteres esperados. O protocolo de RCD desenvolvido neste trabalho apresenta-se como uma alternativa promissora para obtenção de sec-álcoois enantiomericamente puros, possuindo como principal vantagem o uso de catalisadores (VOSO4 e CAL-B) ambientalmente amigáveis, disponíveis comercialmente e que, por serem heterogêneos, tornam o sistema operacional muito prático.
Optically active secondary alcohols are building blocks for several pharmaceutical, agrochemical and food products. Despite the number of methodologies already described to obtain these compounds, it is still necessary to search for more sustainable and cost-effective methodologies. In this context, this work aimed at the development of a new methodology of chemoenzymatic dynamic kinetic resolution (DKR) for the synthesis of enantiomerically pure secondary alcohols. For this, the racemization step was evaluated using hydrated vanadyl sulfate (VOSO4) as heterogeneous catalyst, which was very efficient in the racemization of (S)-1phenylethanol (ee(S) = 1.0% only in 30 minutes, octane, 80 ° C). Then, reaction conditions of this racemization were optimized by varying solvent, temperature and amount of catalyst, and the reaction in heptane at 50 ° C (ee(S) = 4.6%) was select as the optimum condition. Furthermore, the recycling of VOSO4 was also evaluated and this catalyst remained extremely active even after 10 racemization cycles. Then, the DKR reactions were performed in the optimum reaction condition, using rac-1phenylethanol as substrate, immobilized Candida antarctica lipase B (CAL-B) as enantioselective catalyst, VOSO4 as racemization catalyst and evaluating different acyl donors. The reaction with vinyl decanoate was the most efficient, resulting in the product (R)-1-phenylethyl decanoate with 87% conversion and ee > 99%. However, in the recycling of the heterogeneous chemoenzymatic system, there was a significant loss of catalytic activity already in the second cycle. Finally, in the evaluation of the applicability of the DKR protocol developed for secondary alcohols, high conversions (71 to up to 99%) and excellent enantiomeric excesses (up to 99%) were observed for para-substituted aromatic and heteroatomic sec-alcohols, however for sec-alcohols substituted in the side chain were not observed conversion into the expected esters. The DKR protocol developed in this work can be as a promising alternative for obtaining enantiomerically pure sec-alcohols, having as main advantage the use of eco-friendly and commercially available heterogeneous catalysts (VOSO4 and CAL-B), which make the reaction operational system very easy.
Optically active secondary alcohols are building blocks for several pharmaceutical, agrochemical and food products. Despite the number of methodologies already described to obtain these compounds, it is still necessary to search for more sustainable and cost-effective methodologies. In this context, this work aimed at the development of a new methodology of chemoenzymatic dynamic kinetic resolution (DKR) for the synthesis of enantiomerically pure secondary alcohols. For this, the racemization step was evaluated using hydrated vanadyl sulfate (VOSO4) as heterogeneous catalyst, which was very efficient in the racemization of (S)-1phenylethanol (ee(S) = 1.0% only in 30 minutes, octane, 80 ° C). Then, reaction conditions of this racemization were optimized by varying solvent, temperature and amount of catalyst, and the reaction in heptane at 50 ° C (ee(S) = 4.6%) was select as the optimum condition. Furthermore, the recycling of VOSO4 was also evaluated and this catalyst remained extremely active even after 10 racemization cycles. Then, the DKR reactions were performed in the optimum reaction condition, using rac-1phenylethanol as substrate, immobilized Candida antarctica lipase B (CAL-B) as enantioselective catalyst, VOSO4 as racemization catalyst and evaluating different acyl donors. The reaction with vinyl decanoate was the most efficient, resulting in the product (R)-1-phenylethyl decanoate with 87% conversion and ee > 99%. However, in the recycling of the heterogeneous chemoenzymatic system, there was a significant loss of catalytic activity already in the second cycle. Finally, in the evaluation of the applicability of the DKR protocol developed for secondary alcohols, high conversions (71 to up to 99%) and excellent enantiomeric excesses (up to 99%) were observed for para-substituted aromatic and heteroatomic sec-alcohols, however for sec-alcohols substituted in the side chain were not observed conversion into the expected esters. The DKR protocol developed in this work can be as a promising alternative for obtaining enantiomerically pure sec-alcohols, having as main advantage the use of eco-friendly and commercially available heterogeneous catalysts (VOSO4 and CAL-B), which make the reaction operational system very easy.
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Palavras-chave
Biocatálise, Lipase, Catálise heterogênea, Transesterificação, Quiralidade, Biocatalysis, Heterogeneous catalysis, Transesterification, Chirality